Rett syndrome is a progressive neurological disorder and one of the most common causes of mental retardation in females with an incidence of 1:10,000 - 15,000. Included in the phenotype are a low heart rate variability and weak vagal response to hyperventilation and breath holding. This failure of parasympathetic activity to counterbalance sympathetic output has been suggested as a mechanism contributing to the sudden death seen in some cases. Mutations in the methyl-CpG (cytosine-guanine dinucleotide) binding protein 2 (Mecp2) have been observed in almost 80% of Rett syndrome patients. Mecp2 whose gene is on the X chromosome is a nuclear protein, which mediates transcriptional repression. Recently mice have been generated with a null mutation for Mecp2. Heterozygous females (Mecp2 ) develop motor and respiratory symptoms, which resemble those seen in Rett syndrome. The goal of this application is to characterize parasympathetic activity in Mecp2 female mice and to examine synaptic function in neurons of the nucleus of the solitary tract (NTS), which receive afferent input from the aortic depressor nerve. These second order neurons are the first brain stem recipients of baroreceptor afferents and depressed synaptic activity could result in depressed vagal output. Unrestrained mice instrumented with telemetry blood pressure transmitters will be studied for heart rate (from the peak of the systolic pulse) variability before and after administration of the muscarinic cholinergic receptor blocker atropine to remove vagal input. Baroreceptor gain will be determined from changes in heart rate as a function of blood pressure, which will be raised by phenylepherine. Mecp2 +/- females will be compared to wild-type female mice. Horizontal brain stem slices, which contain the tractus and the NTS, will be used for whole cell electrophysiological studies in wild-type and Mecp2 +/- females. Under voltage clamp configuration postsynaptic currents will be recorded after stimulation of the tractus. A variety of electrophysiological criteria will be used to determine if the site of depressed excitatory postsynaptic current in slices from Mecp2 +/- mice is pre- or post-synaptic. These studies will contribute to the understanding of depressed parasympathetic activity in Rett syndrome.